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<p>Hyperglycemia, the defining feature of diabetes mellitus, enhances cancer immune evasion through multiple mechanisms. V-domain immunoglobulin suppressor of T cell activation (VISTA) overexpression in tumor cells induces CD8⁺ T cell exhaustion, thereby promoting immune evasion. However, whether hyperglycemia modulates tumor cell-intrinsic VISTA expression remains unknown. Here, we demonstrate that VISTA expression is upregulated in colorectal cancer (CRC) cells and is regulated by glucose levels. High glucose induces ERK2-VISTA complex formation, enabling ERK2-dependent phosphorylation of VISTA at Ser248. This phosphorylation triggers the recruitment of ubiquitin-specific protease 22 (USP22), which catalyzes Lys258 deubiquitination to prevent ubiquitin-proteasome-mediated degradation, ultimately stabilizing VISTA protein. Endogenous VISTA depletion followed by rescue expression of the phosphorylation-defective mutant VISTA S248A in CRC cells abrogated high glucose-induced VISTA stabilization, promoted CD8⁺ T cell activation and infiltration, and suppressed colorectal tumor growth. Importantly, targeting ERK2-mediated phosphorylation of VISTA, or using the USP22 inhibitor S02, sensitizes tumors to PD-1 blockade therapy in diabetic mice. Furthermore, VISTA is highly expressed and associated with reduced CD8⁺ T cell infiltration in diabetic CRC tissues. Our study demonstrates that hyperglycemia promotes tumor cell-intrinsic VISTA expression, thereby inhibiting CD8⁺ T cell function, and suggests that targeting tumor-intrinsic VISTA may overcome immune evasion in CRC.</p>

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Hyperglycemia drives lmmune evasion in colorectal cancer through VISTA stabilization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月7日

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  • Xin Liu,
  • Qian Liu,
  • Dong Guo,
  • Zezhou Zhao,
  • Jing Wang,
  • Yaoxian Xiang,
  • Kangjie Wang,
  • Lijun Yang,
  • Ke Zhu,
  • Li Wang,
  • Ruofan Li,
  • Xu Gao,
  • Chan Zhang,
  • Yurong Cheng,
  • Dong Yan,
  • Yingying Tong

摘要

Hyperglycemia, the defining feature of diabetes mellitus, enhances cancer immune evasion through multiple mechanisms. V-domain immunoglobulin suppressor of T cell activation (VISTA) overexpression in tumor cells induces CD8⁺ T cell exhaustion, thereby promoting immune evasion. However, whether hyperglycemia modulates tumor cell-intrinsic VISTA expression remains unknown. Here, we demonstrate that VISTA expression is upregulated in colorectal cancer (CRC) cells and is regulated by glucose levels. High glucose induces ERK2-VISTA complex formation, enabling ERK2-dependent phosphorylation of VISTA at Ser248. This phosphorylation triggers the recruitment of ubiquitin-specific protease 22 (USP22), which catalyzes Lys258 deubiquitination to prevent ubiquitin-proteasome-mediated degradation, ultimately stabilizing VISTA protein. Endogenous VISTA depletion followed by rescue expression of the phosphorylation-defective mutant VISTA S248A in CRC cells abrogated high glucose-induced VISTA stabilization, promoted CD8⁺ T cell activation and infiltration, and suppressed colorectal tumor growth. Importantly, targeting ERK2-mediated phosphorylation of VISTA, or using the USP22 inhibitor S02, sensitizes tumors to PD-1 blockade therapy in diabetic mice. Furthermore, VISTA is highly expressed and associated with reduced CD8⁺ T cell infiltration in diabetic CRC tissues. Our study demonstrates that hyperglycemia promotes tumor cell-intrinsic VISTA expression, thereby inhibiting CD8⁺ T cell function, and suggests that targeting tumor-intrinsic VISTA may overcome immune evasion in CRC.